smn circular rnas as potential new targets and biomarkers for sma

Conditions: Spinal Muscular Atrophy

Summary: spinal muscular atrophy (sma) is a life-threatening disease in infancy that is caused by inactivating mutations in the survival motor neuron 1 (smn1) gene1,2. smn1 mutations lead to deficiency in smn protein, which results in degeneration of motor neurons in the spinal cord, progressive muscle weakness and atrophy. the almost identical smn2 gene does not suffice smn function, because skipping of exon 7 in its mrna yields an unstable protein. nevertheless, smn2 represents a disease modifier gene and increasing its expression or rescuing its splicing defect have long been considered elective strategies for sma1,2. after substantial translational research efforts, the first therapies eliciting clinical benefits for sma patients have recently become available3. nusinersen, an antisense oligonucleotide (aso), and risdiplasm, a small molecule, bind the smn2 rna and promote splicing of exon 7. on the other hand, zolgesma, an adeno-associated virus delivering the smn1 gene (scaav9-smn), bypasses the need to correct the splicing defect. nevertheless, none of these therapies currently represents a complete cure for patients, because not all of them respond equally and in a significant portion of patients the symptoms are attenuated but not corrected3. it is believed that early treatment, possibly at a pre-symptomatic stage, would positively affect the clinical response and may significantly improve patient's management. however, another critical point is the current lack of information on the long-term efficacy and safety of the current treatments4. in this scenario, it is likely that further elucidation of the biological functions of the smn genes and the identification of robust biomarkers for stratification of patients will set the ground for more "personalized" therapies, which may account for the clinical variability observed in patients and help improving the therapies in use.

this project aims at investigating the potential value of smn circrnas as biomarkers of sma, in terms of prediction of disease severity and response to therapeutic treatments. in particular, we aim to: 1. evaluate the potential of smn circrnas as biomarkers of sma clinical outcome. we will evaluate which smn circrnas are released in body fluids of sma patients undergoing treatments and whether they display prognostic power as predictors of disease progression and clinical response to therapies. 2. perform a prospective analysis of smn circrnas expression in pre-symptomatic sma patients. we will analyze the expression levels of smn circrnas in body fluids of sma patients identified by neonatal genetic screening. the results of our project may identify new tools to better stratify sma patients and to improve the efficacy of the currently available treatments for this disease.

Eligibility criteria:
inclusion criteria: * genetic diagnosis of sma, without any restrictions for phenotype (i.e. presymptomatic patients, sma 0, sma i, sma ii, sma iii, sma iv patients), number of smn2, age or gender. * treatment with nusinersen or risdiplam or zolgensma. exclusion criteria: unable to provide consent

Keywords: biomarkers, spinal muscular atrophy; outcome